研究领域
Mammalian Bioenergetics: Metabolic Significance and Control of Uncoupling Proteins
Energy conversion processes in mammalian cells are far from perfect. The research conducted in Dr Harper's laboratory focuses specifically on the metabolic pathways that affect efficiency of energy transduction processes within different cells of the body. The cellular organelle 'charged' with the responsibility of energy conversion is the mitochondrion. It is there that the oxidation of various energy substrates converges for the production of the universal energy currency of cells, ATP. The efficiency of mitochondrial ATP synthesis, or oxidative phosphorylation, varies between different tissues of the body; between different metabolic states; and between different disease states (e.g., thyroid disorders).
The overall aim of the research projects conducted in the Harper lab is to better understand the control of cellular energy transduction processes in health and disease.
In particular, Dr. Harper's laboratory investigates the metabolic significance and control of uncoupling proteins (UCPs). UCPs are a subfamily of the mitochondrial carrier protein family and are located in the mitochondrial inner membrane. They have been hypothesized to cause a mitochondrial proton leak, and thereby allow protons to return to the mitochondrial matrix, bypassing ATP synthase. Thus energy substrates are oxidized, and the energy is released (or "wasted") as heat, instead of being converted to ATP. The function of such seemingly wasteful processes is a major interest of the lab. The role of uncoupling proteins in protection from reactive oxygen species, and cell death, is an expanding research interest of the laboratory group, and has implications for an improved understanding of cell death and aging processes.
Dr. Harper's research group uses integrative approaches spanning from bioenergetic studies of isolated mitochondria, to transfected cell cultures, to transgenic mice, and to clinical investigations. Clinical projects are conducted in collaboration with Dr. Robert Dent (Ottawa Hospital), and Dr. Ruth McPherson (University of Ottawa Heart Institute). Experimental techniques include: gene transfection, transgenics and knockouts, self-referencing microelectrode technologies, metabolic control analysis, oxygen and ion-selective electrodes, real-time PCR, Western blotting, and various forms of fluorescence microscopy.
Graduate Student and Postdoctoral Fellow Supervisions
Completed:
11 M.Sc. Shadi MONEMDJOU, 1998; Manon GAGNÉ, 1999; Andreas ANTONIOU, 2001; Darcy MacLELLAN 2007; Sean CRAWFORD, 2009; Carmen ESTEY 2009; Adrienne GOWING, 2010; Cynthia MOFFAT, 2010; Rui ZHANG, 2012; Cyril ADJEITEY, 2013, Skye McBRIDE 2014
6 Ph.D. Shadi MONEMDJOU, 2002; Tia MOFFAT* 2007; Lisa BEVILACQUA, 2007, Sheila COSTFORD, 2008; Brittany BEAUCHAMP 2015; Ghadi ANTOUN, 2016. * co-supervised with Dr. Steffany Bennett.
6 PDF. Céline AGUER; Véronic BEZAIRE; Martin GERRITS; Ryan MAILLOUX; Fiona McMURRAY; Erin SEIFERT; Brianne THRUSH.
Current (In progress):
3 MSc. Corey DeVLUGT; Awa LIAGHATI; Lucien NADEAU (co-supervised with Dr. Céline Aguer)
3 PhD. Georges KANAAN; Rajaa SEBAA; Abi RAJKUMAR (co-supervised with Dr. Frédérique Tesson)
1 PDF. David PATTEN
Undergraduate Research Thesis Student Supervision:
2016-17: Megan MacFarlane; Karan Gandhi; 2015-2016: Bianca ICHIM; Kijoo KIM; Cecile LE; 2014-15: Kris KOMM; Alyssa PEIXOTO; Jessica QUIZI; 2013-14: Olivier CHARETTE; 2012-13: Dhiya HASSAN, William CHEN, 2011-12: Melissa PASQUA, Aline PFEFFERLE; 2010-11: Naveen VENAYAK; 2009-10: Mark BASTIENELLI; Cyril ADJEITEY; Daniela GAMBAROTTA; 2008-9: Marisa ROSSI; Brittany BEAUCHAMP; 2007-8: Sean CRAWFORD, Samantha PREVOST, Benny HILL, Neha SARNA; 2006-7: Carmen ESTEY, Anastasia TOUR; 2005-6: Mitra ABAIEAN, Dimitre RANEV; 2004-5: Basil HUBBARD, Shehla CHAUDHRY; 2003-4: Matthew NIEDZWIECKI, Julie BEAULIEU; 2002-3: Nausheen SIDDIQUI, Marianne McGEE; 2001-2: Audrey NUK, Lorenne DOUCET; 2000-1: Lisa BEVILACQUA; 1999-2000: Veronic BEZAIRE; 1998-9: Andreas ANTONIOU, 1997-8: Shirin LAL; 1996-7: Manon GAGNE, 1995-6: Shadi MONEMDJOU
Current Research Funding
Canadian Institutes of Health Research (CIHR),Natural Sciences and Engineering Research Council (NSERC)
Distinctions:
University Research Chair in Mitochondrial Bioenergetics. 2016-2021
College of Reviewers, Canadian Institutes of Health Research (CIHR) 2014 -
Visiting Research Scholar, Joslin Diabetes Research Center, Harvard Medical School. Boston, MA. Jan. – Dec. 2014
Elected as the Canadian Representative on the (North American) Obesity Society Council. 2012-2015
Elected to the Board of Governors, Canadian Obesity Network, 2012-
Canadian Society for Nutritional Sciences Centrum Award, 2003
近期论文
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Fiona McMurray*, David A. Patten* and Mary-Ellen Harper (2016) Reactive Oxygen Species and Oxidative Stress in Obesity – Recent Findings and Empirical Approaches. Obesity. In press. 016-0678.
Abi Rajkumar*, Gilles Lamothe, Pierette Bolongo, Mary-Ellen Harper, Kristi Adamo, Eric Doucet, Remi Rabasa-Lhoret, Denis Prud'homme, Frederique Tesson. (2016) Acyl-CoA synthetase long-chain 5 genotype is associated with body composition changes in response to lifestyle interventions in postmenopausal women with overweight and obesity: a genetic association study on cohorts Montréal-Ottawa New Emerging Team, and Complications Associated with Obesity. BMC Med Genet. Aug 11 2016;17(1):56.
Kyle Scott, Maria Benkhalti Jandu, Nicholas D. Calvert, Mathieu Paquette, Li Zhen, Mary-Ellen Harper, Osama Y. Al-Dirbashi, and Jean-Marc Renaud. (2016) KATP channel deficiency in mouse FDB causes an impairment of energy metabolism during fatigue. Am. J. Physiol: Cell. In press. C-00137-2015R3.
Amanda Smith, Skye McBride*, Julien L. Marcadier, Jean Michaud, Osama Y. Al-Dirbashi, Jeremy Schwartzentruber, Chandree L. Beaulieu, Sherri L. Katz, FORGE Canada Consortium, Jacek Majewski, Dennis E. Bulman, Michael T. Geraghty, Mary-Ellen Harper, Pranesh Chakraborty , Matthew A. Lines (2016) Severe Neonatal Presentation of Mitochondrial Citrate Carrier (SLC25A1) Deficiency. J. Inher. Metab. Diseases 27: 1-7. June 16, 2016. In press.
Mireille Khacho, Alysen Clark, Devon S. Svoboda, Joelle Azzi, Jason G. MacLaurin, Cynthia Meghaizel, Hiromi Sesaki, Diane C. Lagace, Marc Germain, Mary-Ellen Harper, David S. Park, Ruth S. Slack. (2016) Mitochondrial dynamics impacts stem cell identity and fate decisions by regulating a nuclear transcriptional program. Cell Stem Cell. 19(2):232-47.
Richard B Richardson and Mary-Ellen Harper. (2016) Mitochondrial stress controls the radiosensitivity of the oxygen effect: Implications for radiotherapy. Oncotarget. 7(16):21469-83.
Brittany Beauchamp* and Mary-Ellen Harper. (2016) In utero undernutrition programs skeletal and cardiac muscle metabolism. Frontiers in Physiology, 6:401. doi: 10.3389/fphys.2015.00401. PMID: 26779032.
Michael A. Kennedy, Tia C. Moffat, Kenneth Gable, Karolina Niewola-Staszkowska, Anne Johnston, Corey Nislow, Linda J. Harris, Robbie Loewith, Mary-Ellen Harper, Teresa Dunn, Steffany Bennett and Kristin Baetz. (2016) A signaling lipid associated with Alzheimer’s disease causes mitochondrial dysfunction. Scientific Reports. 6:19332. doi: 10.1038/srep19332.
Ghadi Antoun*, Skye McBride*, Jason R. Vanstone, Turaya Naas, Jean Michaud, Hugh McMillan, Stephanie Redpath, Dennis Bulman, Jason Brophy, FORGE Canada Consortium, Kym M. Boycott, David Dyment, Martin Holcik, Alex Mackenzie, Mary-Ellen Harper§, and Matthew A. Lines§ (2016) Detailed Clinical and Bioenergetic Characterization of Mitochondrial Encephalopathy, Cardiomyopathy, and Immunodeficiency due to FBXL4 deficiency. Journal of Inherited Metabolic Diseases. (Co-senior authors). 27:1-9.
Mirna Azar, Majid Nikpay, Mary-Ellen Harper, Ruth McPherson, and Robert Dent. (2016) Can response to dietary restriction predict weight loss after Roux-en-Y Gastroplasty? Obesity. 24(4):805-11.
Hussein Daoud, Fiona McMurray*, Andrea Yu, Stephanie Luco, Jason Vanstone, Olga Jarinova, Nancy Carson, Kym M Boycott, Christopher Schofield, Mary-Ellen Harper, David A Dyment, Christine M Armour. (2016) Identification of a Pathogenic FTO Mutation by Next-Generation Sequencing in a Newborn with Growth Retardation and Developmental Delay. Journal of Medical Genetics. 53(3):200-7.
Mirna Azar, Majid Nikpay, Mary-Ellen Harper, Ruth McPherson, and Robert Dent. (2015) Adverse Effects of Beta-Blocker Therapy on Weight Loss in Response to a Controlled Dietary Regimen. Can. J. Cardiol. Accepted Oct. 19, 2015. PMID: 26897181.
Ghadi Antoun*, Fiona McMurray*, A Brianne Thrush*, David A Patten, Alyssa Christine Peixoto*, Ruth S Slack, Ruth McPherson, Robert Dent, and Mary-Ellen Harper. (2015) Impaired Mitochondrial Oxidative Phosphorylation and Supercomplex Assembly in Rectus Abdominis of Diabetic Obese Individuals. Diabetologia. 58(12):2861-6.
Jason Vanstone, Amanda Smith, Skye McBride*, Turaya Naas, Martin Holcik, Ghadi Antoun, Mary-Ellen Harper, Jean Michaud, Erick Sell, Pranesh Chakraborty, Martine Tetreault, Jacek Majewski, Stephen Baird, Kym Boycott, David Dyment, and Alex MacKenzie and Matthew Lines*. (2015) DNM1L-related mitochondrial fission defect presenting as refractory epilepsy. Eur. J. Human Genetics Accepted Oct. 14, 2015. [Paper #449-15-EJHGRR]
Denuja Karunakaran, Laura Richards, Michele Geoffrion, Danyk Barrette, Ryan Gotfrit, Mary-Ellen Harper, and Katey Rayner. (2015) Therapeutic Inhibition of miR-33 Promotes Fatty Acid Oxidation but Does Not Ameliorate Metabolic Dysfunction in Diet-Induced Obesity. Arteriosclerosis, Thrombosis, and Vascular Biology. 35(12):2536-43.
Denuja Karunakaran, A. Brianne Thrush*, MA Nguyen, L Richards, Michelle Geoffrion, R Singaravelu, E Ramphos, P Shangari, Michelle Ouimet, John P Pezacki, Katherine J Moore, L Perisic, L Maegdefessel, U Hedin, Mary-Ellen Harper, Katey J Rayner. (2015) Macrophage Mitochondrial Energy Status Regulates Cholesterol Efflux and is Enhanced by Anti-miR33 in Atherosclerosis. Circ Res. 117(3):266-78.
Brittany Beauchamp*, A. Brianne Thrush*, Jessica Quizi*, Ghadi Antoun*, Nathan McIntosh*, Osama Y. Al-Dirbashi, Mary-Elizabeth Patti, and Mary-Ellen Harper. (2015) Undernutrition during pregnancy in mice leads to dysfunctional cardiac muscle respiration in adult offspring. Biosci Rep. Apr 10;35(3). pii: e00200.
Aguer C, McCoin CS, Knotts TA, Thrush AB, Ono-Moore K, McPherson R, Dent R, Hwang DH, Adams SH, Harper ME. Acylcarnitines: potential implications for skeletal muscle insulin resistance. FASEB J. 2015 Jan;29(1):336-45. doi: 10.1096/fj.14-255901. Epub 2014 Oct 23.
Patten DA, Wong J, Khacho M, Soubannier V, Mailloux RJ, Pilon-Larose K, MacLaurin JG, Park DS, McBride HM, Trinkle-Mulcahy L, Harper ME, Germain M, Slack RS. OPA1-dependent cristae modulation is essential for cellular adaptation to metabolic demand. EMBO J. 2014 Nov 18;33(22):2676-91. doi: 10.15252/embj.201488349. Epub 2014 Oct 8.
Thrush AB, Zhang R, Chen W, Seifert EL, Quizi JK, McPherson R, Dent R, Harper ME. Lower mitochondrial proton leak and decreased glutathione redox in primary muscle cells of obese diet-resistant versus diet-sensitive humans. J Clin Endocrinol Metab. 2014 Nov;99(11):4223-30. doi: 10.1210/jc.2014-1726. Epub 2014 Aug 22.
Beauchamp B, Ghosh S, Dysart MW, Kanaan GN, Chu A, Blais A, Rajamanickam K, Tsai EC, Patti ME, Harper ME. Low birth weight is associated with adiposity, impaired skeletal muscle energetics and weight loss resistance in mice. Int J Obes (Lond). 2014 Jul 11. doi: 10.1038/ijo.2014.120. [Epub ahead of print]
Almontashiri NA, Chen HH, Mailloux RJ, Tatsuta T, Teng AC, Mahmoud AB, Ho T, Stewart NA, Rippstein P, Harper ME, Roberts R, Willenborg C, Erdmann J; CARDIoGRAM Consortium, Pastore A, McBride HM, Langer T, Stewart AF. SPG7 variant escapes phosphorylation-regulated processing by AFG3L2, elevates mitochondrial ROS, and is associated with multiple clinical phenotypes. Cell Rep. 2014 May 8;7(3):834-47. doi: 10.1016/j.celrep.2014.03.051. Epub 2014 Apr 24.
Mailloux RJ, Xuan JY, McBride S, Maharsy W, Thorn S, Holterman CE, Kennedy CR, Rippstein P, deKemp R, da Silva J, Nemer M, Lou M, Harper ME. Glutaredoxin-2 is required to control oxidative phosphorylation in cardiac muscle by mediating deglutathionylation reactions. J Biol Chem. 2014 May 23;289(21):14812-28. doi: 10.1074/jbc.M114.550574. Epub 2014 Apr 12.
Khacho M, Tarabay M, Patten D, Khacho P, MacLaurin JG, Guadagno J, Bergeron R, Cregan SP, Harper ME, Park DS, Slack RS. Acidosis overrides oxygen deprivation to maintain mitochondrial function and cell survival. Nat Commun. 2014 Apr 1;5:3550. doi: 10.1038/ncomms4550.
Campbell C, Grapov D, Fiehn O, Chandler CJ, Burnett DJ, Souza EC, Casazza GA, Gustafson MB, Keim NL, Newman JW, Hunter GR, Fernandez JR, Garvey WT, Harper ME, Hoppel CL, Meissen JK, Take K, Adams SH. Improved metabolic health alters host metabolism in parallel with changes in systemic xeno-metabolites of gut origin. PLoS One. 2014 Jan 8;9(1):e84260. doi: 10.1371/journal.pone.0084260. eCollection 2014.
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